1. Technical Field
The present invention relates, in general, to severe combined immunodeficiency disease (SCID) mice and, in particular, to SCID mice engrafted with synovium and the methods of using same.
2. Background Information
Rheumatoid arthritis (RA) and other forms of inflammatory synovitis are debilitating autoimmune diseases. In RA, immune cells (T cells, B cells, monocytes) home to synovial tissues, and there mediate synovial inflammation that eventually leads to joint destruction. Treatments for RA and other types of inflammatory synovitis are only symptomatic and in general do not prevent joint damage. While animal models of animal synovitis exist, these models differ in many aspects from human RA. Currently, there is no animal model of human RA. An ideal in vivo model of human synovitis would include human synovium, yet be readily available in an animal host for study under controlled conditions using pharmacologic agents to induce or inhibit the synovial inflammatory process.
In 1988, McCune and colleagues described a system in which human fetal thymic and fetal liver grafts grew in C.G-17 scid/scid (SCID) mice (McCune et al (1988) Science 241:1632). Adams et al. recently reported that synovium could engraft under the renal capsule of SCID mice but these authors were unable to characterize the grafts or to repeatedly successfully engraft SCID mice with synovium due to sepsis in engrafted animals and recipient death ((Abstract) 54th Meeting American College of Rheumatology, Seattle, Washington, Oct. 27-Nov. 1, 1990).
Applicants have engrafted synovium under the renal capsule of SCID mice, characterized the inflammatory mediators present, and determined the techniques necessary to successfully engraft &gt;90% of animals with synovium (Rendt et al (Abstract) Keystone Symposium, Lake Tahoe, Calif., March 15-21, 1991; Rendt et al Fed. Proc. 1991). Applicants have observed that human synovial tissue grows well in SCID mice, but after 6-10 weeks frequently contains fewer inflammatory cells than the original engrafted tissue. To determine if human T cells can migrate to human synovial grafts in SCID mice, autologous or allogeneic T cells were injected into the peritoneal cavity of SCID mice engrafted with human synovium. After 7 days in vivo, PB human T cells were isolated from grafts, expanded in vitro, and their TCR v.beta. gene usage determined. Unexpectantly, the only other site in which human PB T cells were found 7 days after IP injection was SCID mouse lymph nodes.
Accordingly, the present invention relates, at least in part, to methods of using immunodeficient SCID mice to grow human synovial explants as xenografts. The SCID mice containing the viable human synovial xenografts constitute an in vitro animal model of human synovial disease. This animal model can be used to facilitate the development of new drugs for treatment of RA, and provides a powerful in vivo model with which to study the pathogenesis of RA.